Osteoporosis is a syndrome of excessive skeletal fragility most often resulting from estrogen deficiency and aging. The decline of trabecular bone structure and other aspects of bone quality secondary to estrogen deficiency and aging are suppressed by treatment with anti-resorptive agents (AR) or reversed with an anabolic agent, hPTH (1-34) (AA). Currently, patients with osteoporosis are often "cycled" through these different types of bone active agents for many years with little data to determine if sequential therapies for osteoporosis differentially affect bone strength and quality, or the durability if treatments are withdrawn. We recently reported that both a potent AR and an AA significantly improved trabecular bone mass and bone strength in estrogen deficient old rats compared to osteoporotic controls. However, there were differences between the two types of bone active agents, the AA had a greater increase in trabecular bone mass and whole bone strength than the AR;the potent AR had an overall higher and more consistent values for the localized material properties measured including elastic modulus and degree of bone mineralization (DBM) compared to the AA treated animals. Since these bone active agents augment bone strength by somewhat different mechanisms we hypothesize that in estrogen-deficient old rats: 1. Long-term treatment with potent ARs or an AA will improve localized bone quality and whole bone strength and withdrawal of ARs and an AA will differ in the time to reduction in bone quality and bone strength. 2. Altering the sequence of treatments will also differentially affect localized bone material properties and whole bone strength. To test these hypotheses we propose the following specific aims: 1. To determine the time frame for the deterioration of localized bone quality including the DBM, local microstructural bone tissue material properties, and whole bone strength differs after treatment with either ARs or an AA. 2. To determine if the localized aspects of bone quality including the DBM, local microstructural bone tissue material properties, and whole bone strength differ in estrogen deficient old rats treated sequentially with ARs followed by AA;AA followed by ARs or cyclic therapy with ARs, then AA or vehicle then AR, and ARs alone. 3. To determine if there is an association between the changes in biochemical markers and surface-based bone turnover, bone matrix composition, and localized and whole bone material properties with long term sequential therapies;ARs followed by AA;AA followed by ARs;or cyclic therapy with ARs, AA or vehicle and ARs alone. To accomplish these specific aims we will perform two very large experiments long-term studies using 10-month-old osteopenic rats. We will measure localized microstructural properties and whole bone strength and determine how the localized properties change with different treatment regimens, These preclinical studies will provide data that will guide clinicians in prescribing these bone active agents to maximize bone strength and the durability of their effects. PUBLIC HEALTH RELEVANCE: At least one third of women older than 65 years will experience an osteoporotic fracture. This research has direct relevance to public health by providing data that will guide clinicians in prescribing osteoporosis medication to maximize bone strength and the durability of their effects.